Dynamic genome and transcriptional network-based biomarkers and drugs: precision in breast cancer therapy.

Despite remarkable progress in medium-term overall survival benefit in the adjuvant, neoadjuvant and metastatic settings, with multiple recent targeted drug approvals, acquired resistance, late relapse, and cancer-related death rates remain challenging. Integrated technological systems have been developed to overcome these unmet needs. The characterization of structural and functional noncoding genome elements through next-generation sequencing (NGS) systems, Hi-C and CRISPR/Cas9, as well as computational models, allows for whole genome and transcriptome analysis. Rapid progress in large-scale single-biopsy genome analysis has identified several novel breast cancer driver genes and oncotargets. The exploration of spatiotemporal tumor evolution has returned exciting while inconclusive data on dynamic intratumor heterogeneity (ITH) through multiregional NGS and single-cell DNA/RNA sequencing and circulating genomic subclones (cGSs) by serial circulating cell-free DNA NGS to predict and overcome intrinsic and acquired therapeutic resistance. This review discusses reliable breast cancer genome analysis data and focuses on two major crucial perspectives. The validation of ITH, cGSs, and intrapatient genetic/genomic heterogeneity as predictive biomarkers, as well as the valid discovery of novel oncotargets within patient-centric genomic trials, encouraging early drug development, could optimize primary and secondary therapeutic decision-making. A longer-term goal is to identify the individualized landscape of both coding and noncoding key mutations. This progress will enable the understanding of molecular mechanisms perturbating regulatory networks, shaping the pharmaceutical controllability of deregulated transcriptional biocircuits.

Identification of novel genes by whole-exome sequencing can improve gastric cancer precision oncology.

AIM: By identifying cancer driver genes involved in tumorigenesis, whole-exome sequencing (WES) analyses enable the development of robust biomarkers and novel therapeutic targets to reach precision oncology. PATIENTS & METHODS: WES analyses were performed in matched gastric cancer-normal gastric tissues from two patients. We compared genes highlighted with those of a database and recent WES/whole-genome sequencing studies. RESULTS: We identified 32 highlighted gastric cancer genes, two of these (DEFB118 and RNF43) may provide future potential clinical implications. CONCLUSION: Definitive evidence on extensive genetic heterogeneity suggests the need for large-scale next-generation sequencing studies to validate gastric cancer driver genes catalog. This list represents the foundation for developing genome-based biomarkers to guide precision gastric cancer treatment.

From Clinical Standards to Translating Next-Generation Sequencing Research into Patient Care Improvement for Hepatobiliary and Pancreatic Cancers.

Hepatobiliary and pancreatic (HBP) cancers are associated with high cancer-related death rates. Surgery aiming for complete tumor resection (R0) remains the cornerstone of the treatment for HBP cancers. The current progress in the adjuvant treatment is quite slow, with gemcitabine chemotherapy available only for pancreatic ductal adenocarcinoma (PDA). In the advanced and metastatic setting, only two targeted drugs have been approved by the Food & Drug Administration (FDA), which are sorafenib for hepatocellular carcinoma and erlotinib for PDA. It is a pity that multiple Phase III randomized control trials testing the efficacy of targeted agents have negative results. Failure in the development of effective drugs probably reflects the poor understanding of genome-wide alterations and molecular mechanisms orchestrating therapeutic resistance and recurrence. In the post-ENCODE (Encyclopedia of DNA Elements) era, cancer is referred to as a highly heterogeneous and systemic disease of the genome. The unprecedented potential of next-generation sequencing (NGS) technologies to accurately identify genetic and genomic variations has attracted major research and clinical interest. The applications of NGS include targeted NGS with potential clinical implications, while whole-exome and whole-genome sequencing focus on the discovery of both novel cancer driver genes and therapeutic targets. These advances dictate new designs for clinical trials to validate biomarkers and drugs. This review discusses the findings of available NGS studies on HBP cancers and the limitations of genome sequencing analysis to translate genome-based biomarkers and drugs into patient care in the clinic.

New horizons for targeted treatment of neuroendocrine tumors.

Neuroendocrine tumors (NETs) are rare and heterogeneous tumors and there is a paucity of randomized clinical trials evaluating the different therapeutic strategies. Over recent years, some important molecular aspects have been investigated and multiple targeted therapies are currently available. One of the most promising targets for the therapy of NETs are the mTOR and angiogenic growth factor receptors. The advent of the inhibitors of the mTOR pathway, tyrosine kinase inhibitors and of somatostatin analogs have shown their efficacy in randomized clinical trials in terms of implementing clinical hormone-induced syndromes and progression-free survival of advanced NETs. This article summarizes the standard therapies and new perspectives in NET's treatment, which remains still very heterogeneous and little known entity.

BMI and lymph node ratio may predict clinical outcomes of gastric cancer.

AIM: BMI and the lymph node (LN) ratio can affect short- and long-term outcomes of patients with gastric cancer. PATIENTS & METHODS: This study includes 104 consecutive patients with gastric adenocarcinoma who underwent curative gastrectomy divided in two groups: overweight group (group A) and normal weight group (group B). RESULTS: We found that 53.4% of our patients were overweight (group A). The overall rate of postoperative complications was 16.3%, while mortality was 1%. Statistical analyses revealed that postoperative morbidity was significantly higher in group A (p < 0.05). Long-term survival was significantly higher in group B. Cox regression showed a statistically significant correlation between higher BMI and poor long-term survival after curative gastrectomy. Multivariate analysis has identified age and the LN ratios as independent prognostic factors of survival. CONCLUSION: In this retrospective analysis, BMI and LN ratio were independently associated with survival in patients with gastric cancer. Further studies are needed to confirm our findings.

Intraoperative neuromonitoring of the external branch of the superior laryngeal nerve during thyroidectomy: the need for evidence-based data and perioperative technical/technological standardization.

The external branch of the superior laryngeal nerve (EBSLN) is surgically relevant since its close anatomical proximity to the superior thyroid vessels. There is heterogeneity in the EBSLN anatomy and EBSLN damage produces changes in voice that are very heterogenous and difficult to diagnose. The reported prevalence of EBSLN injury widely ranges. EBSLN iatrogenic injury is considered the most commonly underestimated complication in endocrine surgery because vocal assessment underestimates such event and laryngoscopic postsurgical evaluation does not show standardized findings. In order to decrease the risk for EBSLN injury, multiple surgical approaches have been described so far. IONM provides multiple advantages in the EBSLN surgical approach. In this review, we discuss the current state of the art of the monitored approach to the EBSLN. In particular, we summarize, providing our additional remarks, the most relevant aspects of the standardized technique brilliantly described by the INMSG (International Neuromonitoring Study Group). In conclusion, in our opinion, there is currently the need for more prospective randomized trials investigating the electrophysiological and pathological aspects of the EBSLN for a better understanding of the role of IONM in the EBSLN surgery.

Research and clinical applications of cancer genome sequencing.

PURPOSE OF REVIEW: To highlight the recent advances in cancer genome research and its clinical applications made possible by next-generation sequencing (NGS), with particular emphasis on gynecological and breast cancers is the purpose of the review. RECENT FINDINGS: Through advances in NGS technologies, whole-exome sequencing and whole-genome sequencing (WGS) have been performed on various cancers, identifying in the process numerous recurrent mutations and highly mutated genes. These cancers include uterine serous carcinomas, high-grade serous ovarian adenocarcinomas and breast cancer. In contrast to identifying somatic mutations in sporadic cancers, a far smaller number of studies using NGS have been conducted to identify new causal mutations or genes for hereditary cancer syndromes. In addition to research discovery, diagnostic applications of NGS have also become increasingly evident. Thus, WGS has been applied in a diagnostic context to identify a complex chromosomal rearrangement in a patient with acute myeloid leukemia of unclear subtype. Similarly, the targeted sequencing of panels of known cancer genes using NGS has demonstrated its robustness in the context of identifying known pathological mutations. SUMMARY: The research and clinical applications of cancer genome sequencing have progressed at an unprecedented pace over the last few years, and this promises to be accelerated with new developments of high-throughput NGS technologies and robust analytical tools.

Longitudinal ctDNA profiling in precision oncology and immunο-oncology.

Serial analysis of circulating tumor DNA (ctDNA) over the disease course is emerging as a prognostic, predictive and patient-monitoring biomarker. In the metastatic setting, several multigene ctDNA assays have been approved or recommended by regulatory organizations for personalized targeted therapy, especially for lung cancer. By contrast, in nonmetastatic disease, detection of ctDNA resulting from minimal residual disease (MRD) following multimodal treatment with curative intent presents major technical challenges. Several studies using tumor genotyping-informed serial ctDNA profiling have provided promising findings on the sensitivity and specificity of ctDNA in predicting the risk of recurrence. We discuss progress, limitations and future perspectives relating to the use of ctDNA as a biomarker to guide targeted therapy in metastatic disease, as well as the use of ctDNA MRD detection to guide adjuvant treatment in the nonmetastatic setting.

Gene discovery in familial cancer syndromes by exome sequencing: prospects for the elucidation of familial colorectal cancer type X.

Recent advances in genotyping and sequencing technologies have provided powerful tools with which to explore the genetic basis of both Mendelian (monogenic) and sporadic (polygenic) diseases. Several hundred genome-wide association studies have so far been performed to explore the genetics of various polygenic or complex diseases including those cancers with a genetic predisposition. Exome sequencing has also proven very successful in elucidating the etiology of a range of hitherto poorly understood Mendelian disorders caused by high-penetrance mutations. Despite such progress, the genetic etiology of several familial cancers, such as familial colorectal cancer type X, has remained elusive. Familial colorectal cancer type X and Lynch syndrome are similar in terms of their fulfilling certain clinical criteria, but the former group is not characterized by germline mutations in DNA mismatch-repair genes. On the other hand, the genetics of sporadic colorectal cancer have been investigated by genome-wide association studies, leading to the identification of multiple new susceptibility loci. In addition, there is increasing evidence to suggest that familial and sporadic cancers exhibit similarities in terms of their genetic etiologies. In this review, we have summarized our current knowledge of familial colorectal cancer type X, discussed current approaches to probing its genetic etiology through the application of new sequencing technologies and the recruitment of the results of colorectal cancer genome-wide association studies, and explore the challenges that remain to be overcome given the uncertainty of the current genetic model (ie, monogenic vs polygenic) of familial colorectal cancer type X.

Clinical cancer genome and precision medicine.

Revolutionary sequencing technologies have changed biomedical research and life science exponentially. Revealing the whole landscape of causal somatic and inherited mutations underlying individual patient's cancer sample by whole-genome sequencing (WGS) and whole-exome sequencing (WES) can lead to not only a new mutations-based taxonomy of solid tumors (Stratton, Science 331:1553-1558, 2011). But also shapes a roadmap for precision medicine (Roychowdhury et al., Sci Transl Med 3:111ra121, 2011; Roukos, Expert Rev Mol Diagn 12:215-218, 2012; Mirnezami et al., N Engl J Med 366:489-491, 2012). This inevitable approach for personalized diagnostics in concert with free-falling genome sequencing costs raises now the question of applying next-generation sequencing (NGS) technology in the clinic. In the pragmatic clinical world and in contrast to innovative research, is NGS-based clinical evidence sufficient for decision-making on tailoring the best available treatment to the individual cancer patient?

Translating cancer genomes sequencing revolution into surgical oncology practice.

BACKGROUND: Ten years after the first complete human genome sequencing, next-generation sequencing (NGS) technology has revolutionized genomics and biomedical research. Here we discuss potential emerging and future applications of NGS platforms and how cancer genome advances may change current surgical oncology practice. MATERIALS AND METHODS: Publications in PubMed with partial or complete human and cancer genome sequencing over the last decade have been retrieved and analyzed. Recently launched international large-scale consortiums for systematic study of causal (driver) mutations underlying common complex diseases such as cancer and more recent opinion articles by leading scientists have been considered to predict the prospects of integration genomics data into surgical oncology. RESULTS: Two dozen complete human genome sequences, and three full-genome sequencing in three cancer patients have recently been published. These studies and other cancer genome systematic studies evaluating genomic rearrangements and copy-number changes consistently reveal that cancer initiation and metastasis are much more complex than we thought. This high complexity and widespread variability of cancer genes, mutations, and deregulated signaling pathways among patients with the same cancer type, tumor stage, and clinicopathologic features explains the limited effectiveness of currently used biologically targeted agents. CONCLUSIONS: Yet the impact of genomics explosion in surgical oncology is little. Nevertheless, "big" biology consortiums such as the International Cancer Genome Project and other systematic studies in the areas of genetics, genomics, and epigenetics are now providing in-depth understanding of cancer, and shape new more rational ways towards novel therapeutics for improving oncologic outcomes of millions of patients worldwide. At the beginning of the second post-genomic decade, an explosion in genomic technology has revolutionized biomedical sciences. The ability of latest DNA sequencing technology to identify, in an unprecedented level, causal mutations driving cancer initiation and metastasis raises significant expectations for improving oncologic outcomes. Which are the challenges and perspectives to translate this genomic revolution into a surgical oncology-changing era?